1. Field of the Invention
This invention relates to tetrazolo[a]quinazol-5-one and derivatives thereof and to their use for the control of peptic ulcers and allergic reactions.
2. Description of the Prior Art
Tetrazolo[a]quinazol-5-one, the parent compound of the series of compounds described herein is described by Postovskii et al., Zhur. Obshchei Khim., 33, 2334-2341 (1963) [C.A. 59, 13987a]. Several 4-substituted tetrazolo[a]quinazol-5-ones are described by Vereshchagina et al., Zhur. Obshchei. Khim., 34, 1745-8 (1964) [C.A. 61, 8307-8]. However, these references do not report any utility for the compounds. Neither tetrazolo[a]quinazol-5-one or 7-methoxy-8-n-propoxytetrazolo[a]quinazol-5-one showed bronchodilator activity when tested in guinea pigs by the procedure of Van Arman et al., J. Pharm. Exptl. Therap., 153, 90-7 (1961).
A series of tetrazolo(1,5-c)quinazolin-5(6H)-ones useful as bronchodilators is described in U.S. Pat. No. 3,838,126, issued Sept. 24, 1974.
Allergic reactions, the symptoms resulting from an antigen-antibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders, for example, are allergic rhinitis, a condition characterized by seasonal or perennial sneezing, running nose, nasal congestion, with itching and congestion of eyes; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass pollens; and bronchial asthma, one of the most disabling and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi on exposure to various immunogenic or nonimmunogenic stimuli, resulting in bronchospasms with wheezing, short-lived paroxysms and widespread constriction of airway passages. The mechanical obstruction to airflow in airways is generally reversed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergy agents prevent the release of mediators of anaphylaxis from tissue stores to preclude elicitation of bronchoconstriction by the mediators.
Recently, Cos and co-workers, Adv. in Drug Res., 5, 115 (1970), described the pharmacology of one such agent, disodium cromoglycate [1,3-bis(2-carboxycromon-5-yloxy)-2-hydroxypropane, Intal]. It is not a bronchodilator, but mediates its therapeutic effects by a unique mechanism of action involving inhibition of release of mediators of anaphylaxis and is administered prophylactically. It suffers from lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant. Further, although it is effective against anaphylaxis due to immunoglobulin E (IgE), it is effective against anaphylaxis due to immunoglobulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg./kg.).
Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.
Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common affliction for which a variety of treatments have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers; the most recent of which to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans ("Carbenoxolone Sodium: a Symposium", J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by undesirable aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity, and oftentimes, potassium loss, such that continued therapy with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure.
Carbenoxolone sodium is almost wholly absorbed in the stomach and is not effective against duodenal ulcers except when administered as a specially formulated capsule which enables its transport to the desired site.
A more effective treatment of peptic ulcers is, therefore, desirable. One which will effectively act upon ulcers in the duodenum, as well as upon gastric ulcers, without the need of special formulation and minimizes the aldosterone-like side effects of carbenoxolone is especially desirable.